新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 组学 » PNAS & JACS:重大突破!科学家或将彻底攻克阿尔兹海默氏症

PNAS & JACS:重大突破!科学家或将彻底攻克阿尔兹海默氏症

来源:生物谷 2016-08-08 12:41

图片摘自:neurosciencenews.com

2016年8月8日 讯 /生物谷BIOON/ --阿尔兹海默氏症患者大脑中存在着β淀粉样蛋白的细长纤维(原纤维)形成的典型衰老斑块,近日来自隆德大学和MIT的研究人员通过合作在原子分辨率水平下同时成功阐明了β淀粉样蛋白肽类1-42原纤维的清晰结构,相关研究刊登在了国际杂志PNASJACS上,这两项研究或为后期开发治疗阿尔兹海默氏痴呆症的新型靶向药物提供思路。

在全球阿尔兹海默氏症影响着至少60%的痴呆症患者,其往往让患者遭受着巨大的身体折磨和高额的治疗费用,然而目前并没有有效的疗法来治疗这种顽疾,其中一个原因就是研究者还不能够在分子水平下解析该疾病的发病根源。众所周知β淀粉样蛋白在阿尔兹海默氏症发病过程中扮演着重要的角色,这种39-42个氨基酸长度的肽类对于神经细胞具有毒害作用,而且能够形成细长的纤维;β淀粉样蛋白肽类1-42和β淀粉样蛋白肽类1-40是出现在衰老斑块中的两种主要形式,研究者并不知道为何其会引发大脑神经细胞的退变。

这项研究中,研究人员在原子分辨率的水平下成功对β淀粉样蛋白肽类1-42原纤维进行了成功解析,在阿尔兹海默氏症中这种原纤维结构具有最大的危险性,此前研究中芝加哥大学的研究者解析了β淀粉样蛋白单体的结构,而本文研究就是在此基础上进行的;后期深入的免疫学分析结果也表明,研究者所阐明的这种原纤维结构对于疾病非常关键。蛋白原纤维结构在电子显微镜成像下可见,但在原子水平上却很难解析,当前结构生物学研究中所采用的标准方法就可以完成这种家红色,即高分子作为单晶体而出现或者以溶解在水中的单个分子来出现,然而原纤维是一种可以彼此吸附,要么形成晶体要么溶解在水中的细长形式。

因此,只有固态的核磁共振波谱法(solid-state NMR)能够在原子水平下对原纤维的结构进行成像解析,而这种方法也使得科学家们能够测定组成原纤维的蛋白分子中原子网络中各个原子间的距离,同时大量的计算就可以使得这些原纤维的原子结构被重建。β淀粉样蛋白1-42肽类的主要结构呈现出双马蹄样,一对相同的分子组成层状结构,而这些层状结构互相堆积最终形成细胞的纤维结构,同时大量的氢键同长轴平行使得原纤维结构具有较高的稳定性。研究者Peter Guntert教授解释道,这种原纤维的结构不同于早期模型研究所得到的结构,早期模型研究中很少能够获得实验测定数据。

相关研究结果由隆德大学和MIT的研究人员发现,而且他们互相证实了研究结果,而这两项研究也将让相关的研究领域沸腾,因为这为后期科学家们开发靶向性攻击β淀粉样蛋白纤维的新型疗法提供了一定的线索,研究者坚信在未来10年或者20年里他们获将彻底攻克阿尔兹海默氏症。(生物谷Bioon.com)

本文系生物谷原创编译整理,欢迎转载!点击 获取授权 。更多资讯请下载生物谷APP.

Atomic Resolution Structure of Monomorphic Aβ42 Amyloid Fibrils

Michael T. Colvin†, Robert Silvers†, Qing Zhe Ni†, Thach V. Can†, Ivan Sergeyev∥, Melanie Rosay∥, Kevin J. Donovan†, Brian Michael†, Joseph Wall§, Sara Linse‡, and Robert G. Griffin*†

Amyloid-β (Aβ) is a 39–42 residue protein produced by the cleavage of the amyloid precursor protein (APP), which subsequently aggregates to form cross-β amyloid fibrils that are a hallmark of Alzheimer’s disease (AD). The most prominent forms of Aβ are Aβ1–40 and Aβ1–42, which differ by two amino acids (I and A) at the C-terminus. However, Aβ42 is more neurotoxic and essential to the etiology of AD. Here, we present an atomic resolution structure of a monomorphic form of AβM01–42 amyloid fibrils derived from over 500 13C–13C, 13C–15N distance and backbone angle structural constraints obtained from high field magic angle spinning NMR spectra. The structure (PDB ID: 5KK3) shows that the fibril core consists of a dimer of Aβ42 molecules, each containing four β-strands in a S-shaped amyloid fold, and arranged in a manner that generates two hydrophobic cores that are capped at the end of the chain by a salt bridge. The outer surface of the monomers presents hydrophilic side chains to the solvent. The interface between the monomers of the dimer shows clear contacts between M35 of one molecule and L17 and Q15 of the second. Intermolecular 13C–15N constraints demonstrate that the amyloid fibrils are parallel in register. The RMSD of the backbone structure (Q15–A42) is 0.71 ± 0.12 Å and of all heavy atoms is 1.07 ± 0.08 Å. The structure provides a point of departure for the design of drugs that bind to the fibril surface and therefore interfere with secondary nucleation and for other therapeutic approaches to mitigate Aβ42 aggregation.

Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril

Marielle Aulikki Wältia,1, Francesco Ravottia,1, Hiromi Araib, Charles G. Glabeb,c, Joseph S. Walld, Anja Böckmanne,2, Peter Günterta,f,g, Beat H. Meiera,2, and Roland Rieka,2

Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1–40) and Aβ(1–42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1–42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer’s disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15–42 forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. Residues 1–14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.

相关会议推荐

2016(第二届)生物标志物研讨会

会议时间:2016.09.09-2016.09.10 会议地点:上海

会议详情: http://www.bioon.com/z/2016biomarker/

本网站所有注明“来源:生物谷”或“来源:bioon”的文字、图片和音视频资料,版权均属于生物谷网站所有。非经授权,任何媒体、网站或个人不得转载,否则将追究法律责任。取得书面授权转载时,须注明“来源:生物谷”。其它来源的文章系转载文章,本网所有转载文章系出于传递更多信息之目的,转载内容不代表本站立场。不希望被转载的媒体或个人可与我们联系,我们将立即进行删除处理。
温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库